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Monday, August 20, 2012

Eventful Months for Tekmira

Last week, Tekmira reported its quarterly results and provided a
corporate update. With interim phase I results
for its lead clinical candidate TKM-PLK1, well received clinical results by its licensee
Alnylam, the Stop-Work Order from the Department of Defense, milestone payments
from Talon and Alnylam, and the prospect of a jury trial following a key decision by the judge in the litigation with Alnylam, these certainly must have been one of Tekmira’s busiest 4 months ever.

TKM-PLK1 Results

20 months after trial start, Tekmira finally reported first
data from its lead clinical program, TKM-PLK1 for advanced solid cancers. The most informative data from this early-stage trial, as
expected, related to safety/tolerability and pharmacokinetics.

Accordingly, it appears that the maximally tolerated dose using an aggressive
once-weekly dosing regime is 0.75mg/kg after encountering dose-limiting toxicities in the form of a case of transient
thrombocytopenia and hypoxia/dyspnea each at 0.9mg/kg. These data are in line with the clinical safety/tolerability data from other DlinDMA-based SNALP formulations
(ALN-VSP02, ALN-TTR01) where the maximally tolerated dose was slightly higher,
but which were dosed in in less aggressive schedules.
Although there seems to be a trade-off between dosing frequency and
safety/tolerability, I would agree that for cancer applications where gene
knockdown is targeted in rapidly dividing cells, more frequent
dosing vs higher, but less frequent dosing may be desirable. This is because the duration of gene
knockdown is known to be largely inversely correlated with cell division
frequency.

Looking back at the overall DLinDMA results (ALN-VSP02, ALN-TTR01,
TKM-PLK1), given the fairly uniform maximally tolerated doses, it is possible that lipid-specific toxicity can be as dose-limiting as
siRNA sequence-specific immune stimulations. It
will therefore be interesting to see whether there will be a general shift in
the maximally tolerated dose with SNALP formulations comprising different lipids.

While, as in many of these small, dose escalation trials,
there were encouraging signs of therapeutic efficacy, here in the form of one partial
response by RECIST and one stable disease, what excited me most about the released data was that this particular SNALP formulation achieved ‘several
fold’ higher drug exposure levels than previous formulations (aka ALN-VSP02). High/long exposure levels, of course, are thought to be critical for efficient drug delivery
via the EPR effect. The advance can be
attributed to Tekmira’s rational SNALP design approach involving the use of a long-chain lipid-anchored PEG such that the cloak of invisibility is shed only after longer circulation times. This is unlike in ALN-VSP02 (short chain anchor SNALP formulation) which exhibited short circulation times suitable for RNAi trigger delivery into various hepatic cell types. Similar to
ALN-VSP02 this time, further important pharmacokinetic data showed that the PK profile did not change upon repeat administration. It is therefore unlikely that neutralizing antibodies are generated to the PEG
component. In certain old preclinical studies this had been shown to be an obstacle to repeat administration.

I look forward to learning about the more detailed clinical
results. In particular, I’d like to see
not only the blood PK data, but possibly also the drug accumulations in tumor
biopsies which could be compared to the ALN-VSP02 biopsy data. By this, one would be able to model how
exactly the higher blood exposure levels translate into tumor delivery benefits.

Ebola Stop-Work Order

Earlier this month, Tekmira and competitor Sarepta received Stop-Work
Orders from the US Department of Defense relating to their Ebola biodefense
programs. Tekmira has greatly benefitted
from the DoD contract- not so much in terms of making a direct profit
from the contract, but in that it also provided funding for progressing its
technology platform. A significant
number of employees would have to be laid off if the final decision on whether
to continue with the program, expected by September 1, were negative. Although the impact on Tekmira’s science would
not be immediate, it would definitely impact the speed of Tekmira’s technology
advances if no substitute funding was found soon (see litigation
section). What is particularly
frustrating about this Order is that it comes in the middle of an ongoing
phase I clinical trial (at least wait for the results before making a final
decision) and because budgetary uncertainties, not scientific deficiencies apparently
being the reason for it. Ironically, therehave been two recent outbreaks of Ebola in Africa
highlighting that Ebola is not just a bioterrorist, but also persistent public
health threat.

Tekmira Partners
Celebrate Successes, Company Collects Milestones

The recent past were particularly exciting for Tekmira’s
technology licensees Alnylam and Talon Therapeutics. As discussed on this blog before, the ALN-TTR02
knockdown results, critically enabled by Tekmira’s delivery technology, were
very positively received by the biotech community, including investors. These results also paved the way for the
initiation of a phase II trial of ALN-TTR02 triggering a $1M milestone to
Tekmira. As important as the milestone is
to Tekmira on the eve of the jury trial, once the company has fully recovered
possession of its technology, the liver knockdown results should allow the
company to turn many of those companies on the sidelines into willing customers once there is a resolution to the litigation.

A somewhat unexpected $1M milestone came from Talon
Therapeutics, a small biotech company that had licensed early Tekmira small
molecule liposomal drug candidates. The
milestone was triggered by the FDA approval of one of the licensed product
candidates, Marqibo (liposomal vincristine), for the treatment of advanced Ph-
ALL. In addition, the company is entitled
to receive sales milestones.

All Set for a Jury
Trial

Despite all the important events above, the most important
news regarding the financial viability of the company came when the judge made
the important decision to reject the delay and cost-intensifying tactic (here:
Motion for Summary Judgment) by Alnylam paving the way for a jury trial at the
end of October. As the case will be
tried on all counts and, according to Alnylam’s regulatory disclosure, could cost
the company in excess of $1 billion, you would think that Alnylam has no choice
but to settle the matter (or buy Tekmira). The longer Alnylam waits, the more dearly it is likely to cost them.

In that light, the next 2-3 months should be even more exciting for Tekmira shareholders and hard-working employees.

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